The primary objective of this Project is to study the molecular and cellular mechanisms underlying the chronic actions of cocaine and opiates on the mesolimbic dopamine system, particularly on self-administration behavior mediated in part by this neural pathway. One major focus is on the cAMP system: we have shown that chronic cocaine and morphine administration produces equivalent alterations in the levels of certain G- proteins, adenylate cyclase, and cAMP-dependent protein kinase in the nucleus accumbens (NAc), and equivalent alterations in levels of tyrosine hydroxylase (TH), neurofilaments, and other phosphoproteins in the ventral tegmental area (VTA). To further study whether these adaptations could be involved in the rewarding and addicting actions of these drugs of abuse, we will confirm and extend preliminary observations that self-administered cocaine or opiates produces similar changes in these intracellular messenger proteins as seen previously with forced drug treatments. We will also determine whether forced cocaine or opiate treatments produce similar changes in the mesolimbic dopamine system in the non-human primate. Next, we will further establish correlations between the cAMP system and self-administration (and drug-related behaviors) among individual rats within a single strain and among different inbred strains. Preliminary data demonstrate such correlations for novelty-induced locomotor activity with CAMP-dependent protein kinase in the NAc and TH levels in the VTA for individual Sprague-Dawley rats, and for cocaine self-administration and locomotor activity with the cAMP system in Fischer versus Lewis rat strains. Finally, we will try to obtain direct evidence for a role of the cAMP system in drug-related behaviors by studying the effect of compounds that affect the cAMP system, infused locally into the NAc, on drug self-administration. A second focus of the proposed studies is a possible role of the glutamate system in cocaine and opiate action. Glutamate receptor antagonists have been shown to diminish locomotor sensitization developed in response to stimulants. Our studies will extend these findings by investigating the effect of glutamate antagonists on biochemical effects of cocaine and opiates in the VTA and NAc and on cocaine and opiate self-administration, as well as the influence of cocaine and opiate treatments on the glutamate system. A third focus of the proposed studies is to explore cocaine sensitization by use of the acoustic startle reflex. Cocaine is known to increase the amplitude of acoustic startle, and this effect shows sensitization with repeated cocaine exposure. Evidence suggests that the substantia innominata, a region of the mesolimbic dopamine system, may be one site of cocaine action on the startle pathway. We will investigate the role of D 1 and D2 dopamine receptors, and of the cAMP pathway, in acute cocaine action and sensitization in this brain region. Studies of cocaine regulation of startle offer a novel way to investigate the mechanisms underlying cocaine sensitization mediated via the mesolimbic dopamine system.